Ketoconazole a synthetic antifungal agent that inhibits cytochrome P-450 enzymes required for adrenal androgen synthesis, and when used at high doses inhibit adrenal androgen precursors and results in lowering of serum testosterone levels.

Ketoconazole at 400 mg Q8 hours can cause castrate levels of serum testosterone at 24 hours(Trachtenberg J).

Clinical trials has shown a 62.5% response rate in patients with metastatic prostate cancer with a PSA decrease of 79-90%, median duration of response 3.5 months.

Case reports integrate some patients may have responses in excess of 5 years.

Has a non specific CYP 17 inhibitory property and suppresses androgen biosynthesis when used in high doses

It is non-selective and is associated with modest antitumor efficacy in prostate cancer and significant toxicity as well as interactions with a wide range of medications due to its effect on other CYP enzymes.

Therapy for hormone refractory prostate cancer inhibiting cytochrome P450 14-alpha-demethylase, a catalyst of the conversion of lanosterol to cholesterol.

Inhibits action on cholesterol side chain cleavage enzyme and CYP17 demonstrating secondary hormonal activity in hormonally refractive prostate cancer.

Administered with hydrocortisone to prevent adrenal insufficiency.

Response rate 30-55% in hormone refractory prostate cancer, with a median time to PSA progression of approximately 6 months.

Cancer and Leukemia group B 9583 trial suggested with treatment with Ketoconazole adrenal androgen levels decline in prostate cancer patients and when resistance develops adrenal androgens increase.

Oral absorption impaired by less than an optimal acidic environment and should be taken on an empty stomach without antacids, proton pump inhibitors or H2 blockers.

In a phase III study of patients with hormonally refractive metastatic prostate cancer 28% of patients had greater than 50% decline in PSA level and a median survival of 16 months, and patients with progressive disease, adrenal androgen levels increased, indicating failure of the drug to suppress hormone production long-term (Small EJ).

Ketoconazole is a potent P450 3A4 cytochrome inhibitor that reduces circulating vitamin D-3 levels by 30-40%.

Ketocanazole normalizes urinary free cortisol levels in 50% of patients with Cushing’s disease.

Side effects include nausea, headache, low testosterone levels, reversible elevated liver enzyme levels, and in rare cases hepatotoxicity.

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